1. Field of the Invention
The chemicals of the present combination are used in therapy in man, as of arteriosclerosis, to reduce blood levels of cholesterol, triglycerides and lipo proteins, to increase fibrinolytic activity and to decrease platelet aggregation.
2. Description of the Prior Art
The method of reducing the cholesterol content of blood, particularly in man, which comprises the oral administration of p-chlorophenoxyisobutyric acid (CPIB) and the lower alkyl esters and alkaline earth metal salts thereof including its calcium salt is disclosed in U.K. Patent Specification No. 860,303, Canada Pat. No. 707,737 and U.S. Pat. No. 3,262,850. It is stated therein that:
"The compositions described above may in addition contain dietary supplements, for example, vitamins, salts of glycerophosphoric acid, choline and inositol, the combination of which is known to be effective in reducing serum cholesterol levels, and amino acids, for example, methionine which has a lipotropic action similar to choline."
The ethyl ester has found extensive use in medicine under the generic name of clofibrate (e.g. as "ATROMID-S") and in combination with androsterone (as "ATROMID"). Various amine salts have also been used, e.g. as by Spreafico, Arzneim.-Forsch. 23(2), 236-239 (1973) and so have amides, e.g. U.S. Pat. No. 3,629,453. The aluminum salt is disclosed in Switzerland Pat. Nos. 423,748 and 452,459. Combinations with androstone derivatives are disclosed in U.K. Patent Specification No. 898,596 and with heparinoid in Belgium Pat. No. 669,411.
The utility of oral clofibrate therapy in the management of Fredrickson Type III and Type IV hyperlipemias in humans is well documented; see
Krasno, L. R., and G. J. Kidera: Clofibrate in coronary heart disease. Effect on morbidity and mortality, JAMA 219(7): 845-851 (1972).
Unsigned: Trial of clofibrate in the treatment of ischaemic heart disease. Five-year study by a group of physicians of the Newcastle upon Tyne region, Brit. Med. J. 4: 767-775 (1971).
Unsigned: Ischaemic heart disease? A secondary prevention trial using clofibrate, Report by a research committee committe of the Scottish Society of Physicians, Brit. Med. J. 4: 775-784 (1971). It is firmly established that calcium in the form of calcium carbonate administered orally produces hypochlesteremic effects in human Type II and Type IV hypercholesteremics; see
Bierenbaum, M. L., A. I. Fleischman and R. I. Raichelson: Long term human studies on the lipid effects of oral calcium, LIPIDS 7(3): 202-206 (1972). of the same magnitude as does clofibrate in Types III and IV. To the extent that mechanisms of hypocholesteremic action are known, it appears that each of these agents acts differently from the other, and that the degree of hypocholesteremia induced by each seems to be limited to about 25% (although the degree of hypocholesteremia is highly variable among human subjects). Combinations of hypocholesteremic agents have been strongly suggested as being of potential value in the management and prevention of cardiovascular disease; see
Parson, Jr., W. B.: Treatment of hyperlipidemia: The rationale for combinations of lipid-lowering drugs, Clin. Med.: 15-20, November, 1971.
The desirability of reducing the adhesiveness and aggregation of blood platelets as a method for preventing the formation of thrombi and emoboli in mammals is well-known and has been discussed, for example in U.S. Pat. No. 3,646,195.
Considerable effort has been directed in recent years to obtain substances which are useful in the treatment of hyperlipidemia, a condition associated with elevated cholesterol, phospholipid and/or triglyceride blood levels. This condition is associated with a number of diseases, one of the most serious being atherosclerosis. Medicaments used to lower blood cholesterol, phospholipid and triglyceride blood levels are termed hypolipidemic drugs. Presently four major lipid lowering agents are available; clofibrate, D-thyroxine, nicotinic acid and cholestyramine; [R. I. Levy and D. S. Fredrickson, Postgraduate Medicine, vol. 47, pps. 130-136 (1969)].
Prior to this invention there has been a great need for an effective antihyperlipemic agent which is low in toxicity and is relatively free of undesirable side effects. For example, it is believed that coronary artery disease and atherosclerosis in man are associated with an abnormally high concentration of cholesterol and other lipids in the blood stream. Of particular significance is the concentration of the .beta.-lipoprotein fraction in the blood. The reduction of the amount of these lipids, including not only free and esterified cholesterol, but also phospholipids and triglycerides, is of major importance in the prevention and treatment of coronary artery disease, atherosclerosis, other vascular and heart ailments and disorders of lipid metabolism.
It is therefore an object of this invention to provide a method for reducing plasma lipid levels, particularly cholesterol, triglyceride and phospholipid levels. Another object is to provide a pharmaceutical composition capable of lowering plasma lipid levels when internally administered. Still another object is to provide such reductions without untoward side effects. A further object is to provide pharmaceutical compositions suitable for oral administration. A still further object is to provide such compositions which effectively lower the .beta.-lipoprotein fraction of serum lipids.